Cardiovascular disease (CVD) is increased 50-100% among HIV- infected patients, occurring often among relatively younger HIV patients despite minimal traditional risk factors, and normal LDL. Indeed, the mechanisms of atherogenesis in HIV are unique and relate to increased immune activation, as demonstrated by increased indices of monocyte activation and chemoattraction. Moreover, detailed coronary imaging by cardiac computed tomography angiography (CCTA) demonstrates a significantly increased prevalence of non-calcified plaque, with high risk morphological characteristics, including positive remodeling and low CT attenuation. Despite the significant increase in CVD among HIV-infected patients, no treatment strategies as yet exist to prevent this disease. Treatment with statins represents an attractive option to prevent CVD in HIV. Statins demonstrate potent effects to lower LDL and are known to uniquely reduce monocyte activation, chemoattraction and endothelial activation, potential pathogenetic mechanisms of atherogenesis in HIV. In this grant, we will perform a multicenter, randomized placebo-controlled clinical trial (REPRIEVE) of pitavastatin, as a primary prevention strategy for CVD in HIV. 5300 HIV-infected subjects without known heart disease and with LDL<130 mg/dL and Framingham Risk Score < 20 will be enrolled. Pitavastatin has been shown to safely and effectively lower LDL in HIV and is known to have minimal interactions with antiretroviral therapy. The primary endpoint will be the effects of statin therapy on major adverse cardiac events (MACE) including atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, resuscitated cardiac arrest, nonfatal stroke. In addition, we will perform an embedded mechanistic study among 800 subjects using detailed CCTA imaging and sophisticated biomarker assessments to determine efficacy and mechanisms of statin therapy to reduce non-calcified plaque volume, and high risk morphological features. Change in specific inflammatory biomarkers, including monocyte activation, endothelial activation, arterial inflammation and coagulation, will be determined in the mechanistic study and then assessed with regard to MACE in the primary study, to provide critically needed information on the mechanisms of statin effects in HIV. Detailed safety indices, including effects on glucose homeostasis, liver and muscle will be determined, and effects on non CVD events will be explored. The trial will be performed in collaboration with the AIDS Clinical Trial Group, as well as clinical research sites within the NIAID research network, including sites from the INSIGHT network. With 5300 planned participants the trial is well powered (90%) to detect a HR of 0.65, assuming a baseline event rate of 18/1000 PY. This novel trial will provide much needed information on a critical problem for HIV- infected patients and will serve as a model for the study of tailored primary prevention strategies for other inflammatory diseases in which immune mediated atherogenesis is an important contributing factor.